J Korean Med Sci.  2009 Jan;24(Suppl 1):S135-S142. 10.3346/jkms.2009.24.S1.S135.

Clinical Significance of Monitoring Circulating CD4+CD25+ Regulatory T Cells in Kidney Transplantation during the Early Posttransplant Period

• Kim SH
• Oh EJ
• Ghee JY
• Song HK
• Han DH
• Yoon HE
• Choi BS
• Yoon SK
• Choi JY
• Moon IS
• Kim DG
• Yang CW

• KMID: 1778153
• DOI: http://doi.org/10.3346/jkms.2009.24.S1.S135

Abstract

The CD4+CD25+ T regulatory cells (Tregs) play an important role in immune tolerance in experimental transplantation but the clinical significance of circulating Tregs in the peripheral blood is undetermined. In 50 kidney transplant (KT) recipients, 29 healthy controls and 32 liver transplant (LT) recipients, the frequency of Tregs was measured with flow cytometry before and after transplantation. In the KT recipients, IL-10 secretion was measured with an enzyme-linked immunospot (ELISPOT) assay. The median frequency of circulating Tregs before KT was similar to that in healthy controls but significantly lower than that in LT patients before transplantation. The frequency of Tregs was significantly decreased in patients with subclinical acute rejection compared with those without subclinical acute rejection. Calcineurin inhibitors (CNIs) and anti-CD25 antibody decreased the frequency of Tregs but mTOR inhibitor did not. The frequency of donor-specific IL-10 secreting cells did not correlate with the number of Tregs. The frequency of circulating Tregs in KT recipients is strongly affected by CNIs and anti-CD25 antibody, and a low frequency of Tregs is associated with subclinical acute rejection during the early posttransplant period.

Keyword

T-lymphocytes, Regulatory; Graft Rejection; Interleukin-10; Kidney Transplantation; Kidney Failure, Chronic

MeSH Terms

Adult
CD4-Positive T-Lymphocytes/*immunology
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Graft Rejection
Humans
Interleukin-10/metabolism
Interleukin-2 Receptor alpha Subunit/*biosynthesis
Kidney Failure, Chronic/blood/immunology/*therapy
Kidney Transplantation/*methods
Male
Middle Aged
Nephrology/*methods
T-Lymphocytes, Regulatory/*immunology

Figure

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  Fig. 1 (A) Comparison of the frequency of circulating CD4+CD25+ T regulatory cells (Tregs) in healthy subjecrs (HS) and in patients with end stage renal disease (ESRD) and chronic liver disease (CLD). The frequency of Tregs is expressed as a percentage of peripheral blood mononuclear cells (PBMCs). Median, interquartile range (boxes) and range (whiskers) are shown. #denotes p values <0.01 compared with CLD. *denotes p values <0.001 compared with HC. (B) Comparison of circulating Tregs frequencies based on the underlying disease in patients with ESRD. CGN, chronic glomerulonephritis; DM, diabetes mellitus; LN, lupus nephritis. (C) Comparison of circulating Tregs frequencies based on the underlying disease in patients with CLD. Note the significantly increased Tregs frequency in alcoholic cirrhosis and chronic hepatitis B compared with HC. *denotes p values <0.001. ALC, alcoholic liver cirrhosis; CHB, chronic hepatitis B; Drug, Drug induced hepatitis.

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  Fig. 2 (A) The sequential changes in the frequency of circulating CD4+CD25+ T regulatory cells (Tregs) before and after kidney transplantation. Note the significant decrease in circulating Tregs during the early posttransplant period. (B) The serial measurement of CD4+CD25+ Tregs frequencies in liver transplant (LT) recipients. The frequency of Tregs is expressed as a percentage of peripheral blood mononuclear cells (PBMCs). Median, interquartile range (boxes) and range (whiskers) are shown. *denotes p values <0.001 compared with baseline (pretransplant) level.

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  Fig. 3 The association between the frequency of circulating Tregs and clinical parameters (A-H) in kidney transplant recipients. The frequency of Tregs is expressed as a percentage of peripheral blood mononuclear cells (PBMCs). Median, interquartile range (boxes) and range (whiskers) are shown. Note that there is no significant association between circulating Tregs and clinical parameters (A-G) except subclinical acute rejection (SAR) (H). *denotes p values <0.05 compared with control.

• 

  Fig. 4 Comparison of circulating Tregs frequencies based on type of immunosuppressant (A-C) and drug levels (D and E) in kidney transplant recipients. A significant decrease in circulating Tregs was observed in the FK506 group (A, n=28), and the CsA group (B, n=12) but not in the CsA/mTOR inhibitor group (C, n=10). Patients with a high blood level of FK506 (≥10 ng/mL, n=17) showed a lower frequency of circulating Tregs than did patients with low blood levels of FK506 (<10 ng/mL, n=11) but blood levels of CsA did not affect circulating Tregs. The frequency of Tregs is expressed as the percentage of peripheral blood mononuclear cells (PBMCs). Median, interquartile range (boxes) and range (whiskers) are shown. *denotes p values <0.001 compared with control.

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